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  • VIP and PACAP induce selective neuronal differentiation of mouse embryonic stem cells. 15009127

    The capacity of embryonic stem cells (ES cells) to differentiate into neuronal cells represents a potential source for neuronal replacement and a model for studying factors controlling early stages of neuronal differentiation. Various molecules have been used to induce such differentiation but so far neuropeptides acting via functional G-protein-coupled receptors (GPCRs) have not been investigated. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides expressed in early development which affect neuronal precursor proliferation and neuronal differentiation. VIP and PACAP share two common receptors (VPAC1 and VPAC2 receptors) while only PACAP binds with high affinity to PAC1 receptors. The aim of the study was to determine whether VIP and PACAP could produce functional neuronal differentiation of ES cells. Mouse ES cells were allowed to aggregate in embryoid bodies (EBs) in the presence or not of VIP and PACAP for 1 week. VIP and PACAP potently increased the proportion of EB-derived cells expressing specifically a neuronal phenotype shown by immunocytochemistry and neurite outgrowth without altering glial cell number. Binding and RT-PCR analyses demonstrated the presence of VPAC2 and PAC1 receptors on ES cells. Accordingly, both peptides increased cyclic AMP and intracellular calcium. In contrast, EB-derived cells only expressed a functional PAC1 receptor, suggesting a switch in GPCR phenotype during ES cell differentiation. These original data demonstrate that functional GPCRs for VIP and PACAP are present on ES cells and that these neuropeptides may induce their differentiation into a neuronal phenotype. It opens an exciting new field for neuropeptide regulation of tissue ontogenesis.
    Document Type:
    Reference
    Product Catalog Number:
    MAB353
    Product Catalog Name:
    Anti-Nestin Antibody, clone rat-401

  • Exogenous Administration of PACAP Alleviates Traumatic Brain Injury in Rats through a Mechanism Involving the TLR4/MyD88/NF-κB Pathway. 22583372

    Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) is effective in reducing axonal damage associated with traumatic brain injury (TBI), and has immunomodulatory properties. Toll-like receptor 4 (TLR4) is an important mediator of the innate immune response. It significantly contributes to neuroinflammation induced by brain injury. However, it remains unknown whether exogenous PACAP can modulate TBI through the TLR4/adapter protein myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. In this study, we investigated the potential neuroprotective mechanisms of PACAP pretreatment in a weight-drop model of TBI. PACAP38 was microinjected intracerebroventricularly before TBI. Brain samples were extracted from the pericontusional area in the cortex and hippocampus. We found that TBI induced significant upregulation of TLR4, with peak expression occurring 24 h post-trauma, and that pretreatment with PACAP significantly improved motor and cognitive dysfunction, attenuated neuronal apoptosis, and decreased brain edema. Pretreatment with PACAP inhibited upregulation of TLR4 and its downstream signaling molecules MyD88, p-IκB, and NF-κB, and suppressed increases in the levels of the downstream inflammatory agents interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), in the brain tissue around the injured cortex and in the hippocampus. Administration of PACAP both in vitro and in vivo attenuated the ability of the TLR4 agonist lipopolysaccharide (LPS) to increase TLR4 protein levels. Therefore, PACAP exerts a neuroprotective effect in this rat model of TBI, by inhibiting a secondary inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway in microglia and neurons, thereby reducing neuronal death and improving the outcome following TBI.
    Document Type:
    Reference
    Product Catalog Number:
    MAB377X
    Product Catalog Name:
    Anti-NeuN Antibody, clone A60, Alexa Fluor®488 conjugated

  • Pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptor (PAC1-R) are positioned to modulate afferent signaling in the cochlea. 16876955

    Pituitary adenylyl cyclase-activating polypeptide (PACAP), via its specific receptor pituitary adenylyl cyclase-activating polypeptide receptor 1 (PAC1-R), is known to have roles in neuromodulation and neuroprotection associated with glutamatergic and cholinergic neurotransmission, which, respectively, are believed to form the primary basis for afferent and efferent signaling in the organ of Corti. Previously, we identified transcripts for PACAP preprotein and multiple splice variants of its receptor, PAC1-R, in microdissected cochlear subfractions. In the present work, neural localizations of PACAP and PAC1-R within the organ of Corti and spiral ganglion were examined, defining sites of PACAP action. Immunolocalization of PACAP and PAC1-R in the organ of Corti and spiral ganglion was compared with immunolocalization of choline acetyltransferase (ChAT) and synaptophysin as efferent neuronal markers, and glutamate receptor 2/3 (GluR2/3) and neurofilament 200 as afferent neuronal markers, for each of the three cochlear turns. Brightfield microscopy giving morphological detail for individual immunolocalizations was followed by immunofluorescence detection of co-localizations. PACAP was found to be co-localized with ChAT in nerve fibers of the intraganglionic spiral bundle and beneath the inner and outer hair cells within the organ of Corti. Further, evidence was obtained that PACAP is expressed in type I afferent axons leaving the spiral ganglion en route to the auditory nerve, potentially serving as a neuromodulator in axonal terminals. In contrast to the efferent localization of PACAP within the organ of Corti, PAC1-R immunoreactivity was co-localized with afferent dendritic neuronal marker GluR2/3 in nerve fibers passing beneath and lateral to the inner hair cell and in fibers at supranuclear and basal sites on outer hair cells. Given the known association of PACAP with catecholaminergic neurotransmission in sympathoadrenal function, we also re-examined the issue of whether the organ of Corti receives adrenergic innervation. We now demonstrate the existence of nerve fibers within the organ of Corti which are immunoreactive for the adrenergic marker dopamine beta-hydroxylase (DBH). DBH immunoreactivity was particularly prominent in nerve fibers both at the base and near the cuticular plate of outer hair cells of the apical turn, extending to the non-sensory Hensen's cell region. Evidence was obtained for limited co-localization of DBH with PAC1-R and PACAP. In the process of this investigation, we obtained evidence that efferent and afferent nerve fibers, in addition to adrenergic nerve fibers, are present at supranuclear sites on outer hair cells and distributed within the non-sensory epithelium of the apical cochlear turn for rat, based upon immunoreactivity for the corresponding neuronal markers. Overall, PACAP is hypothesized to act within the organ of Corti as an efferent neuromodulator of afferent signaling via PAC1-R that is present on type I afferent dendrites, in position to afford protection from excitotoxicity. Additionally, PACAP/PAC1-R may modulate secretion of catecholamines from adrenergic terminals within the organ of Corti.
    Document Type:
    Reference
    Product Catalog Number:
    AG305

  • Photic induction of c-Fos in enkephalin neurons of the rat intergeniculate leaflet innervated by retinal PACAP fibres. 17503087

    The brain's biological clock, located in the suprachiasmatic nucleus (SCN), is synchronised with the cyclic environment by photic and non-photic cues. Photic information to the SCN is mediated by pituitary adenylate-cyclase-activating polypeptide (PACAP)-containing retinal ganglion cells (RGCs), whereas non-photic input originates primarily from neuropeptide Y (NPY) cells in the ipsilateral thalamic intergeniculate leaflet (IGL). RGCs also seem to project to the IGL, indicating a role for this structure in the integration of photic and non-photic inputs related to the resetting of the biological clock. In the present study, we have used anterograde tracing from both eyes, bilateral eye enucleation, double-immunofluorescence histochemistry, high-resolution confocal laser scanning microscopy and three-dimensional computer analysis to show that (1) PACAP-containing RGCs project to the IGL and are the only source for the PACAP-immunoreactive fibres in the IGL; (2) a few NPY-containing neurons in the IGL are innervated by PACAP-containing retinal nerve fibres and the contacts are both axodendritic and axosomatic; (3) most enkephalin-immunoreactive neurons in the IGL are innervated by PACAP-containing retinal afferents and the contacts are mainly axodendritic; (4) light stimulation at various time points activates (as evidenced by c-Fos induction) enkephalin-positive neurons but not NPY-immunoreactive neurons. The findings suggest that PACAP-immunoreactive retinal afferents in the IGL primarily innervate enkephalin-immunoactive neurons and that the enkephalin-containing neurons, which project locally and to the contralateral IGL, are activated by light independent of diurnal time.
    Document Type:
    Reference
    Product Catalog Number:
    AB5026

  • PACAP-containing intrapineal nerve fibers originate predominantly in the trigeminal ganglion: a combined retrograde tracing- and immunohistochemical study of the rat. 12932850

    Pituitary adenylate-cyclase activating polypeptide (PACAP) is a neuropeptide originally isolated from the hypothalamus and located in many neuronal systems in both the central and peripheral nervous system. PACAP is also found in nerve fibers innervating the pineal gland, where it stimulates the secretion of the pineal hormone, melatonin, by binding to specific PACAP-receptors located on the cell membrane of the pinealocyte. In this study we have investigated the origin of PACAP-containing nerve fibers innervating the rat pineal gland by combined retrograde tracing with Fluorogold and immunohistochemistry for PACAP. A solution of 2% Fluorogold was injected iontophoretically into the superficial pineal gland of Wistar rats, and the animals were allowed to survive for 1 week. After perfusion fixation of the rats, the location of the tracer was investigated in the brain and the sphenopalatine, otic, and trigeminal ganglia. The tracer was found in all the investigated ganglia. However, colocalization with PACAP was predominantly found in the trigeminal ganglion and only occasionally in the sphenopalatine and otic ganglia. Due to the stimulatory function of PACAP on pineal melatonin secretion, the PACAP-containing neurons of this ganglion could be considered a subset of the parasympathetic nervous system. The presence of neurons with a parasympathetic function in a ganglion that has been considered a purely sensory ganglion, is a new concept in neuroanatomy.
    Document Type:
    Reference
    Product Catalog Number:
    AB153

  • Origin of PACAP-immunoreactive nerve fibers innervating the subarachnoidal blood vessels of the rat brain. 15181370

    The subarachnoidal cerebral blood vessels of the rat are innervated by nerve fibers containing different neuropeptides, e.g. pituitary adenylatecyclase activating polypeptide (PACAP). PACAP dilates brain arterioles and immunohistochemical studies of the rat have indicated that PACAP binds to a VPAC1-receptor in the cerebral vasculature of this species. We have investigated the perikaryal origin of the nerve fibers innervating the subarachnoidal blood vessels of the rat by combined retrograde tracing with Fluorogold and immunohistochemistry. The in vivo neuronal retrograde tracings were done by injection of 2% Fluorogold in water into the subarachnoidal space in the area of the middle cerebral artery. The retrograde transported tracer was detected by use of an antibody against Fluorogold. One week after the injections, the animals were vascularly perfused with Stephanini's fixative and labeled perikarya were found bilaterally in the trigeminal, sphenopalatine, and otic ganglia. The retrograde Fluorogold tracings were combined with immunohistochemistry for PACAP using a mouse monoclonal antibody and the biotinylated tyramide amplification system. Double labeled perikarya containing both Fluoro-gold and PACAP were found predominantly in the trigeminal ganglion, and only rarely in the otic and sphenopalatine ganglion. Summarizing, our retrograde tracings combined with immunohistochemistry indicate that the perikarya in the trigeminal ganglion are the main origin of PACAPergic nerve fibers projecting to the cerebral vasculature of the rat.
    Document Type:
    Reference
    Product Catalog Number:
    AB153

  • Demonstration of PACAP-immunoreactive intrapineal nerve fibers in the golden hamster (Mesocricetus auratus) originating from the trigeminal ganglion. 15683466

    By using immunohistochemistry, a network of nerve fibers containing pituitary adenylate-cyclase activating polypeptide (PACAP) was demonstrated in the pineal gland of the golden hamster, a photoperiodic species often used in pineal and circadian rhythm research. The nerve fibers are present in the capsule from where they permeate into the pineal perivascular spaces and parenchyma. Immuno-electron microscopy showed the PACAPergic nerve terminals, with clear transmitter vesicles, to terminate in the interstitial spaces between the pinealocytes or in the perivascular spaces. Some of the PACAPergic nerve terminals made synapse-like contacts with the pinealocytes. The origin of the PACAP-containing nerve fibers innervating the pineal gland of the hamster was investigated by combined retrograde tracing with fluorogold and immunohistochemistry for PACAP. A 2% fluorogold solution was injected iontophoretically into the superficial pineal gland and the animals were allowed to survive for 1 wk. After perfusion fixation of the rats, the location of the tracer was investigated in the brain, the parasympathetic sphenopalatine, and otic ganglia, as well as in the sensory trigeminal ganglia. The tracer was found in perikarya of all the investigated ganglia. However, co-localization with PACAP was found only in the trigeminal ganglion.
    Document Type:
    Reference
    Product Catalog Number:
    AB153